Project Summary/Abstract A key question is how environmental signals influence health and lifespan in an epigenetic manner. Pheromones are used by many animals, including mammals, to communicate between individuals, and sensing pheromones is known to impact the behavior and even the health of animals. In invertebrates, these inter-individual, pheromone interaction have recently been found to be a means of regulating longevity. We have found that male pheromones shorten the lifespan of the opposite sex in C. elegans (the hermaphrodite). Excitingly, my preliminary data suggests that chemosensation of male pheromones increases the expression of a conserved chromatin modifier (the H3K27me3 demethylase UTX-1) in hermaphrodites. Importantly, changes in utx-1 levels seem to be functionally important in the regulation of longevity; knock-down of utx-1 extends lifespan and promotes stress resistance in the presence and absence of males. Together, these data suggest a model in which changes in the chromatin landscape alter the longevity of an animal in response to male pheromones. The overarching goal of the proposed research is to gain a mechanistic understanding of how chromatin modifiers regulate longevity in response to environmental signals. This proposal uses a highly tractable C. elegans model system to understand how an environmental signal such as pheromones impacts chromatin modifiers and longevity. This proposal will use a combination of genetics, RNAi-based screens, and genomic approaches to uncover the molecular mechanism of chromatin- and pheromone-mediated regulation of longevity. Importantly, many key longevity pathways and genes are well conserved between C. elegans and mammals, including the chromatin modifier upregulated by pheromones (utx-1). The tantalizing idea that pheromones could regulate mammalian longevity has not yet been tested rigorously due to the complexity of inter-individual communication in mammals, and my studies in C. elegans should lay the foundation for future studies in mammals. Furthermore, my proposed research should yield fundamental insights into the role of chromatin the regulation of longevity that will likely have implications for human healthspan and longevity. This proposal builds on my previous research experience and will provide me with technical and intellectual training to prepare me for a career as an independent investigator. My primary mentor, Dr. Anne Brunet, and co-mentor, Dr. Tom Rando, will provide important scientific and career guidance to ensure my success. My advisors and collaborators complement Drs. Brunet and Rando's expertise and will help me reach my career and research goals. The scientific and career development training I will receive during the mentored K99 phase of this award will substantially enhance my current career and research trajectory and will make me a highly competitive candidate for faculty positions at top tier research institutes.